14-69485089-A-G

Position:

• chr14-69485089-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001161498.2(PLEKHD1):​c.124A>G​(p.Arg42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHD1 NM_001161498.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

Genes affected

PLEKHD1 (HGNC:20148): (pleckstrin homology and coiled-coil domain containing D1)

PLEKHD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34255028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHD1	NM_001161498.2	c.124A>G	p.Arg42Gly	missense_variant	1/13	ENST00000322564.9	NP_001154970.1
PLEKHD1	XM_017021290.1	c.-145-15026A>G		intron_variant			XP_016876779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHD1	ENST00000322564.9	c.124A>G	p.Arg42Gly	missense_variant	1/13	1	NM_001161498.2	ENSP00000317175.7
PLEKHD1	ENST00000556123.1	n.398A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.124A>G (p.R42G) alteration is located in exon 1 (coding exon 1) of the PLEKHD1 gene. This alteration results from a A to G substitution at nucleotide position 124, causing the arginine (R) at amino acid position 42 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.024
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.28	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.45
Sift	Benign	0.086	T
Sift4G	Benign	0.12	T
Vest4		0.53
MutPred		0.50		Loss of solvent accessibility (P = 0.0159);
MVP		0.22
ClinPred		0.64	D
GERP RS		2.6
Varity_R		0.15
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-69951806;